1. Field of the Invention
The present invention relates to the field of human and veterinarian medicine. More specifically, the invention relates to prevention and treatment of tissue and organ injury and infection in animals, such as mammals.
2. Discussion of Related Art
Tissue-derived leukocyte chemotactic factors (LCFs) are a group of approximately 3 KDa peptides that are rapidly released by local tissues (within about 5 minutes) in response to injury induced by, for example, chemical agents, such as hydrogen peroxide, sodium hydroxide, citric acid, and alcohol. They are also release in response to physical trauma, such as: scraping; vitamin A deficiency; ultraviolet exposure; ischemia; shear stress; viral infection; and endotoxin treatments. Tissue-derived LCFs were isolated from injured tissues both in vitro using organ culture and cell culture, as well in vivo using animal models and patients with various diseases. Unique tissue-specific LCFs are known to be released by corneal, conjunctival, retinal, heart, coronary arteries, vessels, urinary bladder, brain, spinal cord, and gastric tissues in response to injury.
LCFs are inflammatory mediators that (a) recruit leukocytes from the circulation into sites of infection or tissue injury, (b) stimulate the secretion of adhesion molecules by leukocytes and vascular endothelial cells and accordingly increase the adhesion of cells to the site of injury, and (c) activate leukocytes and vascular endothelial cells to release chemokines, cytokines, and toxic agents such as oxygen metabolites and digestive enzymes.
Various groups have studied LCFs and the inflammation process. For example, U.S. Pat. No. 5,403,914 (herein incorporated by reference) discloses the release of a leukocyte chemotactic factor (LCF) from cardiac tissue in response to injury. The LCF represents the initial signal that recruits leukocytes to the injured tissue. Furthermore, U.S. Pat. No. 5,091,404 (herein incorporated by reference) discloses a system using cyclocreatine to preserve and/or restore the physiological functionality of myocardial tissue subject to ischemia, and particularly tissue subject to reperfusion. The system imparts to the cardiac tissue the ability to sustain high levels of adenosine triphosphate or at least delay the depletion of adenosine triphosphate (ATP) during total ischemia. It delays the development of acidosis and enhances the prompt recovery of tissue function, such as contractility, in such muscle tissue during and following post-ischemic reperfusion.
An inflammatory reaction within tissue is generally characterized by leukocyte infiltration, edema, redness, pain, neovascularization (in advanced cases), and finally impairment of function. Neutrophils are the major inflammatory cells in acute inflammation, while mononuclear cells are the major cells in chronic inflammation. Acute and chronic inflammation are documented to occur after diverse types of tissue injury. When inflammation is controlled, it provides a central host defense. Uncontrolled inflammation, on the other hand, can cause potentially destructive biological responses.
Leukocyte-mediated cell injury is believed to be a major mechanism of tissue injury in acute and chronic inflammation. Leukocytes release cytotoxic compounds, such as reactive oxygen metabolites (e.g., hydrogen peroxide, superoxide anion, and hydroxyl radicals) and digestive proteolytic enzymes (e.g., collagenase and elastase). In the case of reperfusion after ischemia, neutrophils could also be deleterious to injured tissues because of their large size. Neutrophils can plug tissue capillaries during reperfusion resulting in what is known as the “no-reflow” phenomenon with resultant impaired perfusion. Furthermore, activated neutrophils induce extended cell injury during “early reperfusion” after ischemia.
There is a need in the art to provide compositions and methods to inhibit both tissue inflammation and tissue apoptosis. For treatment and prevention of injuries to organs, there is a need to provide compositions and methods to inhibit cytokine storms and organ apoptosis. There is furthermore a need to improve treatment of tissue infections. For example, a current treatment for anthrax infection involves the use of several different antibiotics, used in combination with vaccines. New therapeutic approaches are necessary to better protect anthrax-infected patients from vasculitis, vascular and tissue apoptosis, edema, as well as tissue damage. There is a need in the art to improve treatment of infections in general.
Vaccines and viral medications are the two most common approaches generally used to prevent and treat viral infections, but neither can control the excessive host inflammatory response including cytokine storms, which occur secondary to Avian viral influenza infections and can cause death.
What is particularly needed are methods and compositions that can treat a wide variety of tissue injuries across different mammalian tissues as well as different types, severities, and durations of tissue injuries.